In 1989, a main causative virus of non-A non-B post-transfusion hepatitis was found and named hepatitis C virus (HCV). Since then, several types of hepatitis viruses have been found besides type A, type B and type C, wherein hepatitis caused by HCV is called hepatitis C. The patients infected with HCV are considered to involve several percent of the world population, and the infection with HCV characteristically becomes chronic.
HCV is an envelope RNA virus, wherein the genome is a single strand plus-strand RNA, and belongs to the genus Hepacivirus of Flavivirus (from The International Committee on Taxonomy of Viruses, International Union of Microbiological Societies). Other hepaciviruses, for example, hepatitis B virus (HBV), which is a DNA virus, is eliminated by the immune system, and the infection with this virus ends in an acute infection, with the exception of neonates and infants having yet immature immunological competence. In contrast, HCV somehow avoids the immune system of the host due to an unknown mechanism. Once infected with this virus, even an adult having a mature immune system frequently develops persistent infection.
When chronic hepatitis is associated with the persistent infection with HCV, it advances to cirrhosis or hepatic cancer at a high rate. Enucleation of tumor by operation does not help appreciably, because the patient often develops recurrent hepatic cancer due to the sequela inflammation in non-cancerous parts.
Thus, an effective therapeutic method of treating or controlling hepatitis C is desired. Apart from the symptomatic therapy to suppress inflammation with an anti-inflammatory agent, there is a demand for the development of a therapeutic agent that reduces HCV to a low level free from inflammation and that eradicates HCV. An optimal therapeutic agent would provide a virologic response classified as a “sustained virologic response,” which is defined as undetectable levels of virus in blood six months or more after completing hepatitis C therapy.
At present, a treatment with interferon, as a single agent or in combination with ribavirin, is the only effective method known for the eradication of HCV. However, interferon can eradicate the virus in only about one-third of the patient population. For the rest of the patients, it has no effect or provides only a temporary effect. Therefore, there is a need for an anti-HCV drug to be used in the place of or concurrently with interferon.
Cyclosporine A is well known for its immunosuppressive activity and a range of therapeutic uses, including antifungal, anti-parasitic, and anti-inflammatory as well as anti-HIV activity. Cyclosporine A and certain derivatives have been reported as having anti-HCV activity, see Watashi et al., 2003, Hepatology 38:1282-1288, Nakagawa et al., 2004, Biochem. Biophys. Res. Commun. 313:42-7, and Shimotohno and K. Watashi, 2004, American Transplant Congress, Abstract No. 648 (American Journal of Transplantation 2004, Volume 4, Issue s8, Pages 1-653). Cyclosporine derivatives having HCV activity are known from International Publication Nos. WO2005/021028, WO2006/039668 and WO2006/038088. Cyclosporines in which the 5-Valine nitrogen is substituted by a non-hydrogen substituent are known from Papageorgiou et al, 1997, Bioorganic & Medicinal Chemistry, 5(1): 187-192.